University of Dundee Molecular mechanisms in atopic eczema ...
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University of Dundee
Molecular mechanisms in atopic eczema
Brown, Sara J.
Published in:Journal of Pathology
DOI:10.1002/path.4810
Publication date:2017
Document VersionPeer reviewed version
Link to publication in Discovery Research Portal
Citation for published version (APA):Brown, S. J. (2017). Molecular mechanisms in atopic eczema: insight gained from genetic studies. Journal ofPathology, 241(2), 140-145. https://doi.org/10.1002/path.4810
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Molecular mechanisms in atopic eczema: insight gained from genetic studies
Running title: Molecular genetic mechanisms in eczema
Sara J Brown
Professor of Molecular and Genetic Dermatology, Wellcome Trust Senior Research
Fellow in Clinical Science and Honorary Consultant Dermatologist,
Skin Research Group,
School of Medicine,
Ninewells Hospital & Medical School,
Jacqui Wood Centre level 7,
James Arrott Drive,
University of Dundee,
Dundee DD1 9SY
+44 (0) 1382 383210
ORCID 0000-0002-3232-5251
Conflict of interest statement
The author has filed a patent application (GB 1602011.7) relating to a mechanism for
the gene EMSY in skin; she has received honoraria for invited lectures at the
American Academy of Asthma, Allergy and Immunology annual meetings.
Word count (main text): 2589
This is the peer reviewed version of the following article: ‘Molecular mechanisms in atopic eczema:
insight gained from genetic studies’, Journal of Pathology, which has been published in final form at
http://onlinelibrary.wiley.com/doi/10.1002/path.4810/full. This article may be used for non-
commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Page 2 of 22
Abstract
Atopic eczema (synonymous with atopic dermatitis and eczema) is a common
heterogeneous phenotype with a wide spectrum of severity from mild transient
disease to a severe chronic disorder with atopic and non-atopic co-morbidities.
Eczema is a complex trait, resulting from the interaction of multiple genetic and
environmental factors. Skin as an organ that can be biopsied easily provides the
opportunity for detailed molecular genetic analysis. Strategies applied to the
investigation of atopic eczema include candidate gene and genome-wide studies,
extreme phenotypes and comparative analysis of inflammatory skin diseases.
Genetic studies have identified a central role for skin barrier impairment in eczema
predisposition and perpetuation; this has brought about a paradigm shift in
understanding atopic disease but specific molecular targets to improve skin barrier
function remain elusive. The role of Th2-mediated immune dysfunction is also central
to atopic inflammation and has proved to be a powerful target for biological therapy
in atopic eczema. Advances in understanding eczema pathogenesis have provided
opportunities for patient stratification, primary prevention and therapy development,
but there remain considerable challenges in the application of this knowledge to
optimise benefit for patients with atopic eczema in the era of personalised medicine.
Key words
Atopic eczema, dermatitis, filaggrin, genome-wide, phenotype, skin barrier, therapy,
transcriptome
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Molecular mechanisms in atopic eczema: insight gained from genetic studies
Importance of eczema genetic studies
Atopic eczema (a diagnostic term which is synonymous with ‘atopic dermatitis’ and
‘eczema’) [1] is an itchy inflammatory skin condition associated with significant
morbidity. It is a strongly heritable disease, demonstrating the importance of genetic
mechanisms in pathogenesis, but its rapid rise in prevalence over recent decades
worldwide has also indicated the importance of environmental factors [2].
Atopic eczema is a common disease, affecting up to 25% of school-aged children
(with a range from 0.2% to 24.6% worldwide) [3,4] and up to 10% of adults [5]. It
characteristically presents in childhood and 70% of cases show onset before 5 years
of age [6]. However eczema follows a chronic relapsing and remitting course with
over 10% of cases persisting into adult life or recurring in adulthood [6].
Approximately 40% of patients with eczema have systemic atopic co-morbidities
including asthma, allergic rhinitis and IgE-mediated food allergies [6,7] which
substantially add to the burden of disease. Other co-morbidities have been
suggested from epidemiological studies [8], including depression [9], attention-deficit
hyperactivity disorder [10] rheumatoid arthritis and inflammatory bowel disease [11],
hypertension and obesity [12,13]; however the shared risk factors and
pathomechanisms are unclear.
Despite the high prevalence of eczema, the pathogenesis of this condition remains
incompletely understood. Atopic eczema is a heterogeneous phenotype [14]; it
results from the interplay of skin barrier impairment and immunological dysfunction,
both of which are determined in part by genetic factors (Figure 1). Genetic studies
over recent years have played a major role in transforming the understanding of
atopic eczema from a disease seen as a primarily immune-mediated disorder to one
Page 4 of 22
that may arise from a primary or secondary skin barrier impairment (Figure 1).
However specific immune dysfunction (characterised by a Th2 and Th22 response)
clearly also plays a significant role in the development of atopic eczema.
Strategies for investigation
Atopic eczema is a complex trait, resulting from the interaction of multiple genetic
and environmental risk factors. In parallel with other complex traits, the strategies for
investigating eczema risk have included the study of candidate genes and extreme
phenotypes as well as genome-wide analyses and most recently exome or genome
sequencing (Figure 2). Mouse models have provided some valuable insights; these
are reviewed elsewhere [15] and this review will focus on human studies. Eczema
research has the advantage of relatively easy access to normal as well as diseased
tissue, which has allowed the addition of detailed gene expression studies to aid the
investigation of molecular mechanisms. Finally, eczema can be compared and
contrasted to the second most common inflammatory skin disease, psoriasis, for
further insight into shared and opposing disease mechanisms (Figure 2). Each of
these strategies will be considered, briefly, in turn.
Candidate gene studies
Many candidate genes have been selected for investigation in relation to eczema
pathogenesis because of their theoretical role in epidermal differentiation, skin or
systemic immunity [16]. Notable findings include a role for variants in the genes
encoding interleukin-4 (IL-4), the IL-4 receptor and IL-13 [17,18]; these associations
have been replicated in candidate gene studies and subsequently supported by
Page 5 of 22
genome-wide association loci (see below). However, the strongest association and
that which has been most widely replicated for a candidate gene for atopic eczema is
the gene encoding filaggrin (FLG) [7,19,20]. This protein is expressed in the
epidermal granular layer and has multiple inter-related functions contributing to skin
barrier development and maintenance [21]. The functions of filaggrin include keratin
filament aggregation (from which it derives its name), contribution of hygroscopic and
acidic amino acids to the stratum corneum and anti-microbial effects [22]. Loss-of-
function mutations in FLG are present in up to 10% of the general population; they
cause the common monogenetic dry skin disorder ichthyosis vulgaris [23]. Ichthyosis
vulgaris exhibits a semi-dominant inheritance, such that homozygous (or compound
heterozygous) individuals have the full phenotype of dry scaly skin, hyperlinear
palms and keratosis pilaris, whilst individuals heterozygous for FLG null mutations
have a milder dry (xerotic) and/or ichthyotic skin phenotype [24]. The same null
mutations are found in up to 40% of patients with moderate-severe atopic eczema
and meta-analysis has shown the risk for eczema in an individual carrying one or
more FLG loss-of-function mutation(s) to be increased 3-fold (odds ratio 3.12, 95%
confidence interval 2.57-3.79) [20]. This illustrates a remarkably strong effect for a
single gene in the context of a complex trait. The central effect of filaggrin in skin
physiology has been further demonstrated by a dose-dependent effect of copy
number variation within this repetitive gene sequence [25] and by the effect of atopic
inflammatory cytokines which suppress filaggrin expression in the skin resulting in
additional barrier impairment [26,27].
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Study of extreme phenotypes
Atopic eczema itself varies from a mild, self-limiting skin disease to a severe, chronic
disorder affecting the entire skin surface, with multisystem involvement and life-long
morbidity. However, severe phenotypes with monogenic inheritance have also
offered insight into mechanisms giving rise to atopic skin inflammation. Netherton
syndrome (OMIM #256500) is an autosomal recessive condition caused by
mutations in SPINK5, encoding a serine protease inhibitor, LEKTI. Features of
Netherton syndrome include an ichthyotic (dry, scaly) and eczematous skin
phenotype and markedly raised IgE. Several independent studies have shown an
association between SPINK5 variants and atopic eczema [28-30]. This indicates the
importance of the protease-antiprotease balance in maintaining an optimal skin
barrier function. The control of proteases by protease inhibitors is crucial in the co-
ordinated differentiation and desquamation of the outer epidermis [31] and also plays
an important role in the cutaneous response to allergens, many of which are, or
contain proteases [32].
Another extreme phenotype of atopic skin disease is the syndrome of severe
dermatitis, multiple allergies and metabolic wasting (SAM), for which the genes
DSG1 (encoding desmoglein 1) and DSP (encoding desmoplakin) have each been
implicated [33,34]. Desmosomes are intercellular junctions which provide
mechanical strength to the skin and are degraded in a controlled way during
physiological desquamation [31]; they also play a key role in cell signaling [35]. The
finding of mutations in DSG1 and DSP causing SAM indicates the importance of
desmosomal proteins in protecting against local and systemic atopic inflammation.
Importantly, there are forms of more extreme skin barrier impairment which do not
appear to predispose to atopic inflammation, such as epidermolysis bullosa;
Page 7 of 22
furthermore, recent molecular profiling of patients with several different rare
monogenic ichthyoses has suggested they may share the feature of Th17 immune
activation [36]. This illustrates the complex and specific role of transcutaneous
sensitization in allergic disease.
Genome-wide analyses
The first genome-wide association study (GWAS) for atopic eczema was published
in 2009 representing the white European population [37]; this identified the locus on
chromosome 1q21.3 (the epidermal differentiation complex which includes FLG) as
well as a locus on 11q13.5, in an intergenic region of unknown function; subsequent
GWAS analyses have replicated these findings. A meta-analysis incorporating
published and unpublished data was completed in 2015 [38] which included over 15
million genetic variants in >20,000 cases and >95,000 controls from populations of
European, African, Japanese and Latino ancestry, followed by replication in
>250,000 eczema cases and controls. This powerful meta-analysis detected 10
additional risk loci, bringing the total number of eczema risk loci identified to date to
31. The majority of GWAS loci are in intergenic or intronic regions for which the
function remains unclear, however where functions can be inferred these have
largely been attributed to skin barrier development, innate and acquired immunity.
The most recently identified loci have been proposed to identify genes with roles in
the regulation of innate host defence and T cell function, supporting a possible role
for autoimmune mechanisms in eczema pathogenesis [38,39].
Whole exome sequencing (WES), in which the coding DNA is captured and
sequenced (as opposed to the genotyping of selected single nucleotide variants in
Page 8 of 22
GWAS) has contributed to the diagnosis of extreme phenotypes in rare diseases
(including SAM, described above [34]) and offered greater detail in the search for
rare variants causing common diseases. To date only one small WES study has
been reported for eczema, in which 22 Ethiopian patients with ichthyosis vulgaris
and atopic eczema were sequenced, identifying possible disease-causing variants in
FLG and related genes as well as some novel candidate genes in a rather
heterogeous pattern of risk [40]. Exome sequencing data has been reported for FLG
and related genes [41] as well as for the HLA region [42], however larger studies will
be required to begin to systemically identify rare variants contributing to atopic
eczema. In addition, whole genome sequencing and painstaking functional studies
will be required to fully assess the complex contribution of non-coding genetic
variants, which is anticipated to be substantial [43,44].
Transcriptome analyses
The accessibility of skin tissue has allowed the detailed comparison of gene
expression patterns in lesional (active eczematous skin) compared with non-lesional
(uninflamed skin on a patient with eczema) and normal skin (from a non-atopic
individual). Whole transcriptome analyses, using RNA sequencing techniques
provide more comprehensive assessment and more detailed quantification of mRNA
than previous microarray studies. Several studies have identified networks of
differentially expressed genes involved in keratinocyte differentiation in the
epidermis, innate and acquired immune responses as well as lipid metabolism [45-
47]. Laser capture microdissection has recently been used to separate the dermal
and epidermal gene expression signatures, identifying some novel immune and
barrier genes [48] which require further validation.
Page 9 of 22
Eczema compared and contrasted with psoriasis
The final approach recently used to investigate genetic mechanisms in eczema has
been a comparison of the two most common inflammatory skin diseases: eczema
and psoriasis. These diseases are usually mutually exclusive in clinical practice, but
very rare cases have both eczematous and psoriatic skin lesions simultaneously.
The concept of mutually antagonistic T cells in psoriasis and eczema has been
proposed, being triggered by specific antigens in each disease [49]. On a genome-
wide level the two diseases show considerable overlap in risk loci, including the
epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control
region (chromosome 5q31.1) and the major histocompatibility complex (chromosome
6p21-22). This observation has been used to perform a genome-wide comparative
analysis, to investigate shared and opposing mechanisms leading to eczema or
psoriasis [50]. Notably there were no shared loci with effects operating in the same
direction on both diseases; instead atopic eczema and psoriasis appear to have
distinct genetic mechanisms with opposing effects in pathways influencing epidermal
differentiation and immune response [50].
Application of molecular genetic insights
The strong effect of FLG null mutations on eczema pathogenesis has identified a
clinically relevant sub-group of patients with more significant atopic pathology.
Individuals with one or more loss-of-function mutations in FLG are at increased risk
of early-onset, severe and persistent eczema [51,52]; a greater prevalence of atopic
co-morbidities [7,52,53]; and higher incidence of eczema herpeticum [54], a severe
and potentially life-threatening spread of herpes simplex virus within areas of
Page 10 of 22
inflamed atopic skin [14]. These observations have enabled clinicians to provide
clearer prognostic guidance for patients. Targeted therapeutic intervention to
increase filaggrin expression has been anticipated but has not yet been developed.
The central role of skin barrier impairment in the genetic predisposition to eczema as
well as its acute and chronic pathology has drawn attention to this feature as a
therapeutic target. Skin barrier impairment as defined by trans-epidermal water loss
(TEWL), can be measured non-invasively in vivo and is a feature of atopic skin even
in the absence of active eczema (Figure 1). Furthermore, elevated TEWL is not
solely explained by loss-of-function mutations in FLG; it is apparent as early as two
days after birth and it predates the onset of eczema [55,56]. These observations
have provided rationale for early intervention studies, designed to improve skin
barrier function for the primary prevention of atopic eczema. Two randomised
controlled studies [57,58] have each shown that daily application of emollient to the
whole skin surface beginning within 3 weeks of birth can reduce the incidence of
atopic eczema in high-risk infants by approximately 50%. The authors of the UK
study have now embarked on a larger, more definitive study (‘BEEP’
ISRCTN21528841). This randomised intervention study will include 2 years’ follow
up to assess whether intensive emollient treatment can reduce the incidence of
atopic asthma, hay fever and food allergy, in addition to preventing or delaying the
onset of eczema. The study design includes, in the secondary analyses, stratification
for FLG genotype to test the hypothesis that filaggrin haploinsufficiency (a
genetically-determined reduction in filaggrin expression) affects response to
emollient treatment. If this is the case, future strategies would allow higher-risk
infants to be targeted for primary prevention.
Page 11 of 22
The central role of Th2/Th22 inflammation in eczema pathogenesis was clear before
the genetic studies supported its role and this inflammatory pathway has been at the
forefront of therapeutic trials. The development of dupilumab, a fully human
monoclonal antibody targeting the interleukin-4 receptor to inhibit signalling via IL-4
and IL-13 appears to be a major step forward in treatment [59]. In phase 1 trials,
~85% of patients showed 50% reduction in eczema severity score (compared with
~35% in the placebo group, p<0.001) [60] and phase 2b clinical trials have shown a
dose-dependent response with a rapid onset of effect (within 4 weeks) [61],
emphasising the central role of IL-4 and IL-13 in atopic eczema. Studies of the
efficacy of dupilumab in the paediatric population are currently on-going [62].
In contrast to dupilumab, omalizumab, a recombinant humanized monoclonal
antibody that binds to the high-affinity Fc receptor of IgE, has shown limited efficacy
in the treatment of atopic eczema [63]. The extent of response in different patients is
rather variable and does not appear to correlate with IgE level; instead there is some
evidence that a response to omaluzimab is more likely in patients with disordered
lipid metabolite profiles and in the absence of FLG mutations [64].
Most recently, a phosphodiesterase-4 (PDE-4) inhibitor, crisaborole, which can be
applied topically to the skin, has shown some efficacy in phase III clinical trials [65].
However, atopic eczema continues to lag behind psoriasis in the armamentarium of
biologic treatments and additional agents, targeted at other components of the
inflammatory cytokine network are anticipated. Our understanding of the complex
pathophysiology of eczema would suggest that a bi-pronged approach, targeting
both the immune dysregulation and the skin barrier impairment may be required to
optimise treatment and to gain control of established severe disease.
Page 12 of 22
Opportunities and outstanding challenges
The identification of genetically determined skin barrier dysfunction in eczema
pathogenesis 10 years ago [19] has brought about a paradigm shift in understanding
atopic disease. This in turn has raised the exciting possibility that atopic eczema (as
well as atopic asthma, allergic rhinitis and food allergy) may be treated and/or
prevented by effective barrier protection and/or repair. The challenge remains to
ascertain whether a simple emollient will be sufficient to bring such a therapeutic
effect or whether bespoke molecular interventions are required.
GWAS has indicated many additional risk loci for eczema, but for the majority the
mechanisms leading to atopic skin inflammation remain unknown and the gene-gene
and gene-environment interactions are largely unexplored. Further investigation of
these disease mechanisms offers the opportunity to understand not only eczema but
also the substantial burden of atopic co-morbidities. Furthermore, strategic
developments in drug discovery will allow the application of genetic insight to the
development of novel targeted treatments [66] and in return a better understanding
of genetic mechanisms will facilitate patient stratification in this heterogeneous
phenotype. The ultimate aim of personalised treatment is a genuinely exciting
prospect for the foreseeable future for patients affected by atopic eczema.
Page 13 of 22
Acknowledgements
SJB’s work is funded by: a Wellcome Trust Senior Research Fellowship in Clinical
Science (106865/Z/15/Z); the Manknell Charitable Trust; and Tayside Dermatological
Research Charity.
I am grateful to the Department of Pathology, Ninewells Hospital and Medical School
and the Tayside Biorepository for providing the eczema skin biopsy sample shown in
Figure 2.
Statement of author contributions
This manuscript was planned, written and illustrated by Sara J Brown.
Page 14 of 22
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Figure titles and legends
Figure 1. Simplified representation of inter-related mechanisms in the
pathogenesis of atopic eczema
Genetic studies have identified the role of variants predisposing to skin barrier
impairment, local and systemic atopic inflammation; the penetration of allergens and
irritants can lead to a cycle of acute and chronically relapsing atopic eczema.
Figure 2. Investigative strategies, insights and application of knowledge of
genetic mechanisms in atopic eczema
Skin, as an organ which can be easily biopsied, offers the opportunity for detailed
molecular genetic investigation; this has provided valuable insights to improve our
understanding of eczema pathogenesis, leading to clinical application and a
promising future for personalised medicine. Central panel shows haematoxylin and
eosin stained biopsy (x100 magnification) from the neck skin of a 49 year old male
patient with atopic eczema, showing histological features including hyperkeratosis,
epidermal spongiosis, a reduction in keratohyaline granules and mixed inflammatory
cell infiltrate. GWAS, genome-wide association analysis; WES, whole exome
sequencing.